Abstract
As a gene therapy strategy, RNA interference (RNAi) offers tremendous tumor therapy potential. However, its therapeutic efficacy is restricted by its inferior ability for targeted delivery and cellular uptake of small interfering RNA (siRNA). This study sought to develop a dual-ligand nanoparticle (NP) system loaded with siRNA to promote targeted delivery and therapeutic efficacy. We synthesized a dual receptor-targeted chitosan nanosystem (GCGA), whose target function was controlled by the ligands of galactose of lactobionic acid (LA) and glycyrrhetinic acid (GA). By loading siPAK1, an siRNA targeting P21-activated kinase 1 (PAK1), a molecular-targeted therapeutic dual-ligand NP (GCGA–siPAK1) was established. We investigated the synergistic effect of these two targeting units in hepatocellular carcinoma (HCC). In particular, GCGA–siPAK1 enhanced the NP targeting ability and promoted siPAK1 cell uptake. Subsequently, dramatic decreases in cell proliferation, invasion, and migration, with an apparent increase in cell apoptosis, were observed in treated cells. Furthermore, this dual-ligand NP gene delivery system demonstrated significant anti-tumor effects in tumor-bearing mice. Finally, we illuminated the molecular mechanism, whereby GCGA–siPAK1 promotes endogenous cell apoptosis through the PAK1/MEK/ERK pathway. Thus, the dual-target property effectively promotes the HCC therapeutic effect and provides a promising gene therapy strategy for clinical applications.
Highlights
Hepatocellular carcinoma (HCC), as one of the most common cancers, is the fourth-leading cause of tumor-related deaths (Villanueva, 2019)
Obtaining similar results in all groups indicates that the additional modifications in the CS does not likely influence the accumulated release of the small interfering RNA (siRNA)
To investigate the molecular mechanism whereby GCGA– siPAK1 promotes cell apoptosis, we introduced bcl2 family members, which are widely associated with the regulators of cell death through the endogenous apoptotic pathways
Summary
Hepatocellular carcinoma (HCC), as one of the most common cancers, is the fourth-leading cause of tumor-related deaths (Villanueva, 2019). As a precise gene therapy treatment strategy, RNA interference (RNAi) has attracted increasing attention in the recent years (Li et al, 2017; Jain et al, 2018; Uludag et al, 2019). The siRNA motivates the sequence-specific enzymolysis effect of the target mRNA by means of complementary base pairing and suppresses the target gene expression (Tavernarakis et al, 2000; Elbashir et al, 2001). This valuable approach circumvents the limitations of conventional systemic chemotherapy and offers a safe tumor therapeutic strategy, without toxic side effects (Chalbatani et al, 2019). As a type of oligonucleotide molecule, siRNA is restricted by its susceptibility to serum degradation and inferior cellular uptake ability when it is practically applied (de Wolf et al, 2007)
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